Project Summary The clinical onset of type 1 diabetes is characterized by the destruction of the insulin-producing ? cells of the pancreas, and is caused by autoantigen-induced inflammation (insulitis) of the islets of Langerhans. The current standard of care for type 1 diabetes mellitus (T1D) patients allows for management of the disease with exogenous insulin, but patients eventually succumb to many chronic complications such as limb amputation, blindness and kidney failure. Currently, there are no effective treatments for the autoimmunity that causes the disease, and any future regenerative or replacement therapies to restore ? cell function will need to be coupled with either immunosuppressive or immunoprotective therapy. Generalized immunosuppressive therapies are impractical for long-term care, and there remains a critical need to develop targeted therapies to treat diabetes- causing autoimmunity. To address this important challenge to the treatment of type 1 diabetes, I propose the development of novel islet-targeted conjugates, nanomaterials, and targeting ligands to localize immunosuppressive agents to the islet microenvironment and enable drug release upon the onset of islet inflammation.